# Re-Tooling of γδ T Cells for Cancer Immunotherapy Using Advanced Manufacturing and Genetic Engineering

**Authors:** Benjamin J. L. Lim, John Maher

PMC · DOI: 10.3390/cells15060494 · 2026-03-10

## TL;DR

This paper reviews the potential of γδ T cells for cancer immunotherapy and how genetic engineering and manufacturing can improve their effectiveness.

## Contribution

The paper evaluates γδ T cells as a promising alternative to CAR T cells and discusses strategies to enhance their therapeutic potential.

## Key findings

- Vδ2 cells are the main circulatory γδ T cell subtype.
- Vδ1 cells show strong tissue tropism.
- Genetic engineering and manufacturing can boost γδ T cell potency for cancer treatment.

## Abstract

What are the main findings?
Vδ2 cells are the predominant circulatory subtype.Vδ1 cells are highly tissue tropic.

Vδ2 cells are the predominant circulatory subtype.

Vδ1 cells are highly tissue tropic.

What are the implications of the main findings?
Allogeneic γδ T cells are under development for cancer immunotherapyInnovative genetic engineering and manufacturing strategies may be used to boost potency.

Allogeneic γδ T cells are under development for cancer immunotherapy

Innovative genetic engineering and manufacturing strategies may be used to boost potency.

Adoptive immunotherapy using ex-vivo-amplified autologous αβ T cells has achieved notable success in the treatment of diverse cancer types. Pre-eminent among these developments has been the advent of chimeric antigen receptor (CAR) T cell therapy, which has revolutionised the treatment of selected haematological malignancies. However, autologous CAR T cell immunotherapy is poorly scalable and has demonstrated limited efficacy against solid tumours. Accordingly, there has been significant interest in alternative strategies that may bridge these gaps. The use of γδ T cells is an attractive alternative since they possess intrinsic anti-tumour activity and do not elicit graft versus host disease (GvHD) when employed as an allogeneic drug product. In this review, we evaluate the potential use of γδ T cells for cancer immunotherapy and how manufacturing and genetic engineering refinements can be used to potentiate this activity. We also summarise current clinical experience with CAR γδ T cell therapies and discuss the implications of these findings for the next generation of cellular immunotherapies.

## Linked entities

- **Diseases:** cancer (MONDO:0004992)

## Full-text entities

- **Genes:** CISH (cytokine inducible SH2 containing protein) [NCBI Gene 1154] {aka BACTS2, CIS, CIS-1, G18, SOCS}, CXCR3 (C-X-C motif chemokine receptor 3) [NCBI Gene 2833] {aka CD182, CD183, CKR-L2, CMKAR3, GPR9, IP10-R}, CD86 (CD86 molecule) [NCBI Gene 942] {aka B7-2, B7.2, B70, BU63, CD28LG2, CD86 v6}, PDCD1 (programmed cell death 1) [NCBI Gene 5133] {aka ADMIO4, AIMTBS, CD279, PD-1, PD1, SLEB2}, CD80 (CD80 molecule) [NCBI Gene 941] {aka B7, B7-1, B7.1, BB1, CD28LG, CD28LG1}, CD70 (CD70 molecule) [NCBI Gene 970] {aka CD27-L, CD27L, CD27LG, LPFS3, TNFSF7, TNLG8A}, CD3E (CD3 epsilon subunit of T-cell receptor complex) [NCBI Gene 916] {aka CD3epsilon, IMD18, T3E, TCRE}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, SLC3A2 (solute carrier family 3 member 2) [NCBI Gene 6520] {aka 4F2, 4F2HC, 4T2HC, CD98, CD98HC, MDU1}, MSLN (mesothelin) [NCBI Gene 10232] {aka MPF, SMRP}, FASLG (Fas ligand) [NCBI Gene 356] {aka ALPS1B, APT1LG1, APTL, CD178, CD95-L, CD95L}, AREG (amphiregulin) [NCBI Gene 374] {aka AR, AREGB, CRDGF, SDGF}, KLRC1 (killer cell lectin like receptor C1) [NCBI Gene 3821] {aka CD159A, NKG2, NKG2A}, MR1 (major histocompatibility complex, class I-related) [NCBI Gene 3140] {aka HLALS}, FOXP3 (forkhead box P3) [NCBI Gene 50943] {aka AIID, DIETER, IPEX, JM2, PIDX, XPID}, FDPS (farnesyl diphosphate synthase) [NCBI Gene 2224] {aka FPPS, FPS, POROK9}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, BTN3A1 (butyrophilin subfamily 3 member A1) [NCBI Gene 11119] {aka BT3.1, BTF5, BTN3.1, CD277}, NUCLEOLIN (nucleolin multifunctional protein) [NCBI Gene 4691] {aka C23, NCL, Nsr1}, BTN2A1 (butyrophilin subfamily 2 member A1) [NCBI Gene 11120] {aka BK14H9.1, BT2.1, BTF1, BTN2.1, DJ3E1.1}, FCGR1A (Fc gamma receptor Ia) [NCBI Gene 2209] {aka CD64, CD64A, FCG1, FCGR1, FCRI, FcgammaRI}, GZMB (granzyme B) [NCBI Gene 3002] {aka C11, CCPI, CGL-1, CGL1, CSP-B, CSPB}, NCAM1 (neural cell adhesion molecule 1) [NCBI Gene 4684] {aka CD56, MSK39, NCAM}, TRBV20OR9-2 (T cell receptor beta variable 20/OR9-2 (non-functional)) [NCBI Gene 6962] {aka CDR3, TCRBV20S2, TCRBV2O, TCRBV2S2O}, PRKAB1 (protein kinase AMP-activated non-catalytic subunit beta 1) [NCBI Gene 5564] {aka AMPK, HAMPKb}, PAG1 (phosphoprotein membrane anchor with glycosphingolipid microdomains 1) [NCBI Gene 55824] {aka CBP, PAG}, CD226 (CD226 molecule) [NCBI Gene 10666] {aka DNAM-1, DNAM1, PTA1, TLiSA1}, TNFRSF9 (TNF receptor superfamily member 9) [NCBI Gene 3604] {aka 4-1BB, CD137, CDw137, ILA, IMD109}, HLA-G (major histocompatibility complex, class I, G) [NCBI Gene 3135] {aka MHC-G}, TNFSF10 (TNF superfamily member 10) [NCBI Gene 8743] {aka APO2L, Apo-2L, CD253, TANCR, TL2, TNLG6A}, ABCA1 (ATP binding cassette subfamily A member 1) [NCBI Gene 19] {aka ABC-1, ABC1, CERP, HDLCQTL13, HDLDT1, HPALP1}, Nr1i3 (nuclear receptor subfamily 1, group I, member 3) [NCBI Gene 12355] {aka CAR, CAR-beta, Care2, ESTM32, MB67}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, EPHA2 (EPH receptor A2) [NCBI Gene 1969] {aka ARCC2, CTPA, CTPP1, CTRCT6, ECK}, KRT20 (keratin 20) [NCBI Gene 54474] {aka CD20, CK-20, CK20, K20, KRT21}, CD83 (CD83 molecule) [NCBI Gene 9308] {aka BL11, HB15}, APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, CARS1 (cysteinyl-tRNA synthetase 1) [NCBI Gene 833] {aka CARS, CYSRS, MCDDBH, MDBH, MGC:11246}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, APOA1 (apolipoprotein A1) [NCBI Gene 335] {aka AMYLD3, HPALP2, apo(a)}, CD38 (CD38 molecule) [NCBI Gene 952] {aka ADPRC 1, ADPRC1, cADPR1}, CD247 (CD247 molecule) [NCBI Gene 919] {aka CD3-ZETA, CD3H, CD3Q, CD3Z, CD3ZETA, IMD25}, CXADRP1 (CXADR pseudogene 1) [NCBI Gene 653108] {aka CAR, CXADRP}, ITGAE (integrin subunit alpha E) [NCBI Gene 3682] {aka CD103, HUMINAE}, CD58 (CD58 molecule) [NCBI Gene 965] {aka LFA-3, LFA3, ag3}, HCST (hematopoietic cell signal transducer) [NCBI Gene 10870] {aka DAP10, KAP10, PIK3AP}, NCR1 (natural cytotoxicity triggering receptor 1) [NCBI Gene 9437] {aka CD335, LY94, NK-p46, NKP46}, MSH2 (mutS homolog 2) [NCBI Gene 4436] {aka COCA1, FCC1, HNPCC, HNPCC1, LCFS2, LYNCH1}, CD33 (CD33 molecule) [NCBI Gene 945] {aka CD33rSiglec, SIGLEC-3, SIGLEC3, p67}, IL3RA (interleukin 3 receptor subunit alpha) [NCBI Gene 3563] {aka CD123, IL-3R-alpha, IL3R, IL3RAY, IL3RX, IL3RY}, CD28 (CD28 molecule) [NCBI Gene 940] {aka IMD123, Tp44}, BTN3A2 (butyrophilin subfamily 3 member A2) [NCBI Gene 11118] {aka BT3.2, BTF4, BTN3.2, CD277}, TGFBR2 (transforming growth factor beta receptor 2) [NCBI Gene 7048] {aka AAT3, FAA3, LDS1B, LDS2, LDS2B, MFS2}, TIGIT (T cell immunoreceptor with Ig and ITIM domains) [NCBI Gene 201633] {aka VSIG9, VSTM3, WUCAM}, CXCR4 (C-X-C motif chemokine receptor 4) [NCBI Gene 7852] {aka CD184, D2S201E, FB22, HM89, HSY3RR, LCR1}, CD1D (CD1d molecule) [NCBI Gene 912] {aka R3, R3G1}, IL18 (interleukin 18) [NCBI Gene 3606] {aka IGIF, IL-18, IL-1g, IL1F4}, IL9 (interleukin 9) [NCBI Gene 3578] {aka HP40, IL-9, P40}, KLRK1 (killer cell lectin like receptor K1) [NCBI Gene 22914] {aka CD314, D12S2489E, KLR, NKG2-D, NKG2D}, SLC2A1 (solute carrier family 2 member 1) [NCBI Gene 6513] {aka CSE, DYT17, DYT18, DYT9, EIG12, GLUT}
- **Diseases:** ADI-001 (MESH:D015431), Cancer (MESH:D009369), glioblastoma (MESH:D005909), hypoxia (MESH:D000860), neuroblastoma (MESH:D009447), autoimmune (MESH:D001327), GBM (MESH:D005910), metabolic dysfunction (MESH:D008659), acute myeloid leukaemia (MESH:D054218), lung adenocarcinoma (MESH:D000077192), absence seizure (MESH:D004832), B cell acute lymphoblastic leukaemia (MESH:D015456), inflammatory (MESH:D007249), B cell malignancies (MESH:D016393), solid (MESH:D018250), leukaemias (MESH:D015458), osteosarcoma (MESH:D012516), lymphoma (MESH:D008223), B-NHL (MESH:D008228), GvHD (MESH:D006086), triple-negative breast cancer (MESH:D064726), AICD (MESH:D003643), follicular lymphoma (MESH:D008224), lung and liver cancers (MESH:D008175), prostate cancer (MESH:D011471), metastases (MESH:D009362), AML (MESH:D015470), B-ALL (MESH:D015452), injury to (MESH:D014947), acidosis (MESH:D000138), cytokine release syndrome (MESH:D000080424), pancreatic cancer (MESH:D010190), CRC (MESH:D015179), cell and plasma cell malignancies (MESH:D007952), hepatocellular carcinoma (MESH:D006528), non-small cell lung cancer (MESH:D002289), cytotoxicity (MESH:D064420)
- **Chemicals:** temozolomide (MESH:D000077204), alendronic acid (MESH:D019386), ZOL (MESH:D000077211), Vitamin C (MESH:D001205), metformin (MESH:D008687), prostaglandin E2 (MESH:D015232), oxygen (MESH:D010100), BrHPP (MESH:C429553), OKT3 (MESH:D016853), ADI (-), lipid (MESH:D008055), Mevalonate (MESH:D008798), hydroxyapatite (MESH:D017886)
- **Species:** human gammaherpesvirus 4 (Epstein Barr virus, no rank) [taxon 10376], Cytomegalovirus (genus) [taxon 10358], Vesicular stomatitis virus (species) [taxon 11276], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606]
- **Cell lines:** T2 — Mus musculus (Mouse), Transformed cell line (CVCL_6C58), K562 — Homo sapiens (Human), Blast phase chronic myelogenous leukemia, BCR-ABL1 positive, Cancer cell line (CVCL_0004)

## Figures

2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13025538/full.md

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Source: https://tomesphere.com/paper/PMC13025538